Rationale:
Preeclampsia (PE) is a potentially life-threatening, placenta-based hypertensive disorder during pregnancy, and the antiphospholipid syndrome (APS) frequently leads to PE. APS pregnancies are also complicated by fetal demise and intrauterine growth restriction (IUGR).
Objective:
Here we determined how the circulating antiphospholipid antibodies (aPL) characteristic of APS alter placental trophoblast function to cause PE and also endanger the fetus.
Methods and Results:
Experiments were performed in mice, in cultured human trophoblasts, and in human placenta samples. Effects of aPL and IgG from healthy subjects were compared. Based on prior findings in culture, in vivo studies were done in mice deficient in apolipoprotein E receptor 2 (ApoER2) in trophoblasts. Endpoints in tissues and cells were determined by enzymatic assay, Q-PCR, ELISA or immunoblotting. Whereas in wild-type mice aPL caused maternal hypertension and proteinuria, fetal demise and IUGR, mice lacking trophoblast ApoER2 were protected. In culture aPL attenuated trophoblast proliferation and migration via an ApoER2-related protein complex comprised of the protein phosphatase PP2A, Dab2, and JIP4. Via trophoblast ApoER2 in mice and in culture, aPL stimulated PP2A activity, leading to MMP14 and HIF1alpha upregulation and increased soluble endoglin (sEng) production. HIF1alpha and sEng upregulation was related to PP2A desphosphorylation of PHD2. In mice PP2A inhibition prevented aPL-induced maternal hypertension and proteinuria, and fetal demise and IUGR. Placentas from APS patients displayed PP2A hyperactivation, PHD2 dephosphorylation and HIF1α upregulation, and these findings were generalizable to placentas of women with PE from causes other from APS.
Conclusions:
In APS pregnancies trophoblasts are the critical cell target of aPL, and via ApoER2-dependent PP2A activation, aPL cause PE through MMP14 upregulation and PHD2 dephosphorylation leading to HIF1 and sEng upregulation. Moreover, parallel processes may be operative in PE in non-APS patients. Interventions targeting PP2A may provide novel means to combat APS-related PE and PE unrelated to APS.
Uterine Rupture at a Site Distant From Old Scar: An Unusual Presentation
